In the recent past, multidrug-resistant Staphylococcus aureus (MDR S. aureus) and especially methicillin-resistant Staphylococcus aureus (MRSA) has been a major health problem affecting population worldwide. The MDR S. aureus burden has continued to be reported in healthcare and community environments between 2015 and 2025 and is becoming more resistant to a variety of antibiotic groups that complicate treatment and control. This review will summarize the epidemiological patterns of the world, local inequalities, molecular pathways of resistance, clinical and population health outcomes, and new treatment options regarding MDR S. aureus. Surveillance data indicates that MRSA has been observed to show a high prevalence of hospital-associated infections with a continued increase in community transmission, as well as a high heterogeneity between low- and middle-income and high-income countries. The appearance and spread of dominant clonal lineages, which are propelled by mobile genetic elements and horizontal gene transfer, have led to resistance beyond β-lactams and also the macrolide, fluoroquinolones, aminoglycosides, and tetracyclines. MDR S. aureus infections are related to treatment failure, extended hospitalization, morbidity, and mortality, as well as significant economic impact. The existing treatment strategies are limited by the resistance of antibiotics, a limited antimicrobial development flow, and the problems of diagnosis and the use of antibiotics in an abused manner. The promising alternatives are anti-virulence therapies, bacteriophage therapy, CRISPR-based antimicrobials, antimicrobial peptides, microbiome-based therapy, and artificial intelligence-based drug discovery. In order to curb the increasing threat of MDR-S. aureus, strengthening antimicrobial surveillance, infection control measures and stewardship programs and coordinated global research and policy efforts is necessary.